Background and Purpose The approved small-molecule inhibitors of
anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some
subset of cancer patients. However, the numerous ALK mutants or fusion
partners are resistant to such drugs, greatly limiting their application
in clinic. Despite the drug design strategy of proteolysis-targeting
chimera (PROTAC) holds great potential to overcome drug resistance in
theory, there are obvious disadvantages for the reported PROTACs that
include high molecular weight, long linkers, difficult synthesis routes
as well as insufficient evidence in activity for diverse ALK mutants.
Experimental Approach In this study, we synthesized a miniaturized
PROTAC of ALK named AP-1 following the principle of minimalist design.
Two simple chemical units of ligands and a minimized linker with only
two atoms were selected for synthesis of AP-1. Key Results At cellular
level, AP-1 successfully degraded three types of ALK mutants including
NPM-ALK, EML4-ALK and F1174L mutation ALK form with strong activity,
high selectivity in ALK-positive cells. In tumor-bearing mouse models,
AP-1 showed the stronger antitumor efficacy than controls as well as the
similar compounds reported in literatures. Conclusion and Implications
AP-1 with an extremely simple PROTAC structure can be served as an
effective candidate drug for therapy of various types of ALK-positive
cancers. And the design principle of AP-1 has a good guiding
significance for overcoming the disadvantages such as excessive
molecular weight and poor solubility of PROTAC.